@article{479a8308ed2e448ca631b6f56a48bf57,
title = "Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling",
abstract = "Cyclic adenosine diphosphate (ADP)–ribose (cADPR) isomers are signaling molecules produced by bacterial and plant Toll/interleukin-1 receptor (TIR) domains via nicotinamide adenine dinucleotide (oxidized form) (NAD+) hydrolysis. We show that v-cADPR (2′cADPR) and v2-cADPR (3′cADPR) isomers are cyclized by O-glycosidic bond formation between the ribose moieties in ADPR. Structures of 2′cADPR-producing TIR domains reveal conformational changes that lead to an active assembly that resembles those of Toll-like receptor adaptor TIR domains. Mutagenesis reveals a conserved tryptophan that is essential for cyclization. We show that 3′cADPR is an activator of ThsA effector proteins from the bacterial antiphage defense system termed Thoeris and a suppressor of plant immunity when produced by the effector HopAM1. Collectively, our results reveal the molecular basis of cADPR isomer production and establish 3′cADPR in bacteria as an antiviral and plant immunity–suppressing signaling molecule.",
author = "Manik, {Mohammad K.} and Yun Shi and Sulin Li and Zaydman, {Mark A.} and Neha Damaraju and Samuel Eastman and Smith, {Thomas G.} and Weixi Gu and Veronika Masic and Tamim Mosaiab and Weagley, {James S.} and Hancock, {Steven J.} and Eduardo Vasquez and Lauren Hartley-Tassell and Nestoras Kargios and Natsumi Maruta and Lim, {Bryan Y.J.} and Hayden Burdett and Landsberg, {Michael J.} and Schembri, {Mark A.} and Ivan Prokes and Lijiang Song and Murray Grant and Aaron DiAntonio and Nanson, {Jeffrey D.} and Ming Guo and Jeffrey Milbrandt and Thomas Ve and Bostjan Kobe",
note = "Funding Information: We acknowledge use of the Australian Synchrotron MX facility and thank the staff for their support. We acknowledge the Centre for Microscopy and Microanalysis, University of Queensland (UQ), and staff (L. Brillault, M. Floetenmeyer, R. Webb, and R. Wepf). We thank F. Makino (JEOL) for help with cryo-EM data collection; K. Arachchige and J. Clegg (UQ) for help with crystallization; F. Rose (Griffith University) for help with HPLC purification of 2′cADPR and 3′cADPR; and M. Mobli (UQ) for advice on NMR. The work was supported by the National Health and Medical Research Council (NHMRC) (grants 1196590 to T.V., 1107804 and 1160570 to B.K. and T.V., 1071659 to B.K., and 1108859 to T.V.); an Australian Research Council (ARC) Future Fellowship (FT200100572 to T.V.); an ARC Laureate Fellowship (FL180100109 to B.K.); an ARC Discovery Early Career Researcher Award (DE170100783 to T.V.); the National Institutes of Health (R01NS087632 to J.M. and A.D.); and the Biotechnology and Biological Sciences Research Council (BB/ V00400X/1 to M.Gr. and L.S.). Y.S. was a recipient of a Griffith University Postdoctoral Fellowship Scheme. Nebraska Soybean Board project no. 1734 funded the research assistantship for S.E. Publisher Copyright: {\textcopyright} 2022 American Association for the Advancement of Science. All rights reserved.",
year = "2022",
month = sep,
day = "30",
doi = "10.1126/science.adc8969",
language = "English",
volume = "377",
journal = "Science",
issn = "0036-8075",
number = "6614",
}